Aquaporin4 (AQP4), a water channel protein, is mainly expressed in the central nervous system, especially in the foot processes of astrocytes surrounding capillaries, beneath pia matter, and lining the ventricles. It plays a crucial role in brain water homeostasis and is involved in the "glymphatic system", which is hypothesized to facilitate waste clearance from the CNS [1,2].

AQP4 has been implicated in various neurological conditions. In Alzheimer's disease, an extended form of AQP4 may increase the clearance of amyloid-β peptides, suggesting its potential as a therapeutic target [2]. In neuromyelitis optica spectrum disorder (NMOSD), most patients have pathogenic antibodies targeting AQP4, which disrupts the blood-brain barrier, impairs glutamate homeostasis, and induces cell death [3,4]. In depression, pre-clinical studies on AQP4 wild-type and knockout (KO) models showed that stress or inflammation decreased AQP4 expression in certain brain regions, and AQP4 expression was necessary to prevent stress-induced depressive-like behaviors [5]. In glioma, AQP4 expression is associated with malignancy, and its subcellular mislocalization may impact glioma progression [7].

In conclusion, AQP4 is essential for maintaining brain water balance and waste clearance. Studies using KO and other genetic models have revealed its significant roles in multiple neurological diseases such as Alzheimer's, NMOSD, depression, and glioma. Understanding AQP4 function through these models provides insights into disease mechanisms and potential therapeutic strategies.

References:

1. Yasui, Masato. . [Aquaporin4 (AQP4) in brain disorder]. In Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 153, 231-234. doi:10.1254/fpj.153.231. https://pubmed.ncbi.nlm.nih.gov/31092756/

2. Mohaupt, Pablo, Vialaret, Jérôme, Hirtz, Christophe, Lehmann, Sylvain. 2023. Readthrough isoform of aquaporin-4 (AQP4) as a therapeutic target for Alzheimer's disease and other proteinopathies. In Alzheimer's research & therapy, 15, 170. doi:10.1186/s13195-023-01318-2. https://pubmed.ncbi.nlm.nih.gov/37821965/

3. Wright, Sukhvir K, Wassmer, Evangeline, Vincent, Angela. 2021. Pathogenic antibodies to AQP4: Neuromyelitis optica spectrum disorder (NMOSD). In Biochimica et biophysica acta. Biomembranes, 1863, 183772. doi:10.1016/j.bbamem.2021.183772. https://pubmed.ncbi.nlm.nih.gov/34509490/

4. Prasad, Sashank, Chen, John. 2019. What You Need to Know About AQP4, MOG, and NMOSD. In Seminars in neurology, 39, 718-731. doi:10.1055/s-0039-3399505. https://pubmed.ncbi.nlm.nih.gov/31847043/

5. Genel, Oktay, Pariante, Carmine M, Borsini, Alessandra. 2021. The role of AQP4 in the pathogenesis of depression, and possible related mechanisms. In Brain, behavior, and immunity, 98, 366-377. doi:10.1016/j.bbi.2021.08.232. https://pubmed.ncbi.nlm.nih.gov/34474133/

6. Jarius, Sven, Wildemann, Brigitte. . AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. In Nature reviews. Neurology, 6, 383-92. doi:10.1038/nrneurol.2010.72. https://pubmed.ncbi.nlm.nih.gov/20639914/

7. Lan, Yu-Long, Zou, Shuang, Chen, Ruoli. 2024. Update on the intriguing roles of AQP4 expression and redistribution in the progression and treatment of glioma. In Annals of medicine, 56, 2401111. doi:10.1080/07853890.2024.2401111. https://pubmed.ncbi.nlm.nih.gov/39247976/